Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site.

Pohlenz, Joachim; Rosenthal, Ira M.; Weiss, Roy E.; Jhiang, Sissy; Burant, Charles F.; Refetoff, Samuel

doi:10.1172/jci1504

Cited by 107 publications

(65 citation statements)

References 29 publications

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“…The resulting impairment in I − uptake in the thyroid leads to congenital hypothyroidism, which, unless treated early in life by TH administration, causes goiter and even mental retardation. Study of the 14 ITD-causing NIS mutations identified to date (27)(28)(29)(30)(31)(32)(33)(34)(35)(36) has been instrumental in the identification of residues key for NIS transport activity (5, 16, 17, 22-25, 37, 38). For example, the analysis of T354P revealed the role in NIS function of TMS9, where this mutation is located (23).…”

Section: Significancementioning

confidence: 99%

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Ferrandino

Nicola

Sánchez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The sodium/iodide symporter (NIS) mediates active I− transport in the thyroid—the first step in thyroid hormone biosynthesis—with a 2 Na+: 1 I− stoichiometry. The two Na+ binding sites (Na1 and Na2) and the I− binding site interact allosterically: when Na+ binds to a Na+ site, the affinity of NIS for the other Na+ and for I− increases significantly. In all Na+-dependent transporters with the same fold as NIS, the side chains of two residues, S353 and T354 (NIS numbering), were identified as the Na+ ligands at Na2. To understand the cooperativity between the substrates, we investigated the coordination at the Na2 site. We determined that four other residues—S66, D191, Q194, and Q263—are also involved in Na+ coordination at this site. Experiments in whole cells demonstrated that these four residues participate in transport by NIS: mutations at these positions result in proteins that, although expressed at the plasma membrane, transport little or no I−. These residues are conserved throughout the entire SLC5 family, to which NIS belongs, suggesting that they serve a similar function in the other transporters. Our findings also suggest that the increase in affinity that each site displays when an ion binds to another site may result from changes in the dynamics of the transporter. These mechanistic insights deepen our understanding not only of NIS but also of other transporters, including many that, like NIS, are of great medical relevance.

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Section: Significancementioning

confidence: 99%

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Ferrandino

Nicola

Sánchez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…O alelo aberrante, derivado do pai, apresentava comprometimento codificando proteína inativa, enquanto o alelo materno exibia mutação que originava o NIS incompleto (31). No Japão, foram descritas várias outras famílias (figura 1) e duas novas mutações, que alteravam aminoácidos na proteína comprometendo sua habilidade em transportar iodeto (32,33).…”

Section: Diagnóstico Molecular Apresentação Clínicaunclassified

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Rubio¹,

Knobel²,

Nascimento³

et al. 2002

Arq Bras Endocrinol Metab

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RESUMOO hipotireoidismo congênito (HC), detectado em recém-nascidos rastreados ao nascer, é causado por anomalias na organogênese (agenesia, tireóide ectópica, hipoplasia tireóidea) ou por defeitos específicos na hormonogênese. Mais raramente, o hipotireoidismo congênito tem origem em defeitos genéticos centrais, localizados no eixo hipotálamo-hipófise ou em mutações do gene do TSH-beta ou no receptor de TSH. Defeitos específicos da hormonogênese são causados por mutações no gene codificador para a proteína transportadora de iodeto (NIS), no gene da peroxidase (TPO), no gene traduzindo a pendrina (síndrome de Pendred), no gene da tireoglobulina, além de mutações que afetam o receptor de hormônio tireóideo (resistência genética ao HT) ou aos vários defeitos no transporte de HT na circulação periférica. Na maioria dos casos, os defeitos genéticos indicados criam condições para fenótipo com bócio e grau variável de hipotireoidismo, podendo a mutação genética ter expressão variável durante a vida adulta. Congenital hypothyroidism (CH), as seen in the neonatal period, is predominantly caused by defects in the organogenesis (athyreosis, ectopic thyroid, thyroid hypoplasia) or by specific defects in hormonogenesis (dyshormonogenesis). Central hypothyroidism is rare, being linked to specific transcription factors involved in the maturation of the hypothalamic-pituitary axis or by mutations in the TSH-beta gene. Dyshormonogenesis may be caused by mutation coding for thyroid proteins such as the TSH receptor, the sodium-iodide symporter (NIS), the pendrin (Pendred's syndrome), thyroid peroxidase (TPO), thyroglobulin (Tg), thyroid dehalogenase, the receptor for thyroid hormone (TR-beta) or thyroid transport proteins (TBG, transthyretin). Usually, most of these defective genes will induce a phenotype with goiter and variable degree of hypothyroidism that may be present in the neonatal period or will gradually develop during post-natal life. Moreover, the genetic expression may be partial or total according to the specific mutation occurring in the involved genes.

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“…About half of these inherited thyroid diseases are caused by an iodide organification defect, characterized by the reduced ability to retain iodide in the thyroid gland. In thyroid follicular cells, iodide is actively transported inside through the sodium iodide symporter (Dai et al 1996, Pohlenz et al 1998. Covalent binding of the iodide to the tyrosine residues (iodide organification) within the thyroglobulin (Tg) molecule and its subsequent coupling yields the thyroid hormones thyroxine (T 4 ) and triiodothyronine (T 3 ).…”

Section: Introductionmentioning

confidence: 99%

Mutation analysis of thyroid peroxidase gene in Chinese patients with total iodide organification defect: identification of five novel mutations

Wu¹,

Shu²,

Yang³

et al. 2002

Journal of Endocrinology

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Total iodide organification defect (TIOD), where the iodide in the thyroid gland cannot be oxidized and/or bound to the protein, is caused by a defect in the thyroid peroxidase (TPO) gene. Single strand conformation polymorphism analysis was used to screen for mutations in the TPO gene from five unrelated TIOD patients in Taiwan, and five novel mutations were detected. Three of these were frameshift mutations: a single T insertion between nucleotide position 2268 and 2269 (c.2268-2269 insT) in exon 13 and two single C deletions at nucleotide positions 843 (c.843 delC) and 2413 (c.2413 delC) in exon 8 and 14 respectively. The other two were single nucleotide substitutions (c.G1477>A and c.G2386>T) located in exons 9 and 13 respectively. While the former would result in amino acid substitution (Gly493Ser) in the highly conserved region of the TPO polypeptide, the latter would result in either amino acid substitution (Asp796Tyr) or alternative splicing. Of those identified TPO mutations, c.2268-2269 insT was most prevalent and was detected as heterozygous in all but one TIOD patients. All five TIOD patients investigated in this study were compound heterozygous. The method presented in this study could be used for carrier assessment and mutation analysis of newly identified TIOD patients.

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Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site.

Cited by 107 publications

References 29 publications

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Mutation analysis of thyroid peroxidase gene in Chinese patients with total iodide organification defect: identification of five novel mutations

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Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site.

Cited by 107 publications

References 29 publications

Na + coordination at the Na2 site of the Na + /I − symporter

Na + coordination at the Na2 site of the Na + /I − symporter

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Mutation analysis of thyroid peroxidase gene in Chinese patients with total iodide organification defect: identification of five novel mutations

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Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter